PROJECT ABSTRACT An emerging body of evidence suggests there is increased morbidity and mortality among human immunodeficiency virus (HIV)-exposed uninfected infants (HEUs) compared to infants born to HIV-uninfected women (HUU). With the HEU child population increasing at >1 million/year, identifying modifiable mechanisms underlying these disparities is a global health priority. Several studies suggest that during pregnancy complicated by maternal HIV infection, exposure to co-pathogens induces placental immune activation, which may alter placental signaling affecting fetal immunity. One such co-infection is human cytomegalovirus (HCMV). Epidemiologic studies have reported that HCMV co-infection may contribute to HIV disease progression and increased mortality. We recently identified the presence of CD8+ T cells in placental villi from pregnant, South African women living with HIV (PWLHIV) and HCMV co-infection, compared to placentae from HIV-uninfected women who were HCMV positive. We hypothesize that there is recruitment and migration of maternally-derived HCMV-specific CD8+ T cells from the uterine decidua to placental villi. We posit that trophoblasts promote migration of antigen-specific CD8+ T cells into the fetal villi compartment, which further exacerbates the inflammatory cascade and promotes apoptosis of trophoblast cells. In order to validate our hypothesis, we will enroll pregnant women attending prenatal care in Cape Town, South Africa, into two groups: 1) HIV/HCMV co-infected pregnant women; and 2) women with HCMV infection only. We will determine the origin, phenotype and epitope specificity of these infiltrating T cells, as well as examine the role of trophoblasts in recruiting these T cells into the villous space. The proposed studies will provide a deeper conceptual understanding of the in vivo effects of maternal HIV/HCMV co-infection during pregnancy on placental immunity. These studies could facilitate the development of immunomodulatory and antiviral therapies targeting inflammation and HCMV, respectively, which may improve clinical outcomes in HEU infants from HIV- and HCMV-coinfected pregnant women.